Document text
Principal Investigator: Neil King
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2022
Award: $792,967
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY – PROJECT 2: Structure-based antigen and nanoparticle vaccine design
Project 2 is focused on the design, production, and characterization of novel stabilized antigens and broadly
protective nanoparticle vaccines. In Aim 1, we will establish automated computational pipelines that identify
sets of novel prefusion-stabilizing mutations in the spike proteins of various sarbecovirus, merbecovirus, and
embecovirus strains we will use in our broadly protective vaccines. Our recent work has also demonstrated the
utility of using deep mutational scanning data to guide the identification of stabilizing mutations in isolated
SARS-CoV-2 receptor-binding domains (RBD). The computational pipelines we develop will extend this
method to the design of additional stabilized RBD antigens across all four known clades of sarbecoviruses for
use in pan-sarbecovirus vaccines. In Aim 2, we will computationally design novel self-assembling protein
nanoparticle scaffolds that present prefusion spike trimers in arrays specifically designed to allow
unconstrained B cell receptor/antibody access to broadly conserved epitopes. We hypothesize that these
scaffolds will elicit antibody responses with superior protective breadth, particularly when used as the basis for
mosaic nanoparticle immunogens. We will experimentally validate several novel nanoparticles and prototype
their functional performance as monovalent nanoparticle immunogens in immunization and challenge studies
in mice to identify the scaffolds that best focus the humoral immune response on conserved epitopes. In Aim 3
we will build on our recent work demonstrating the elicitation of broadly protective immune responses against
influenza by generating multivalent nanoparticle vaccines displaying multiple coronavirus RBDs or prefusion
spikes. We will take a hierarchical, phylogeny-driven approach. We will focus at first on developing a
pan-sarbecovirus vaccine, which will display multiple RBD or prefusion spike antigens. We will then generate
broadly protective merbecovirus and embecovirus vaccines displaying multiple prefusion spikes. Finally, we will
define the optimal composition of a pan-betacoronavirus nanoparticle vaccine. We will work closely with the
other groups in our Program to identify lead pan-sarbecovirus and pan-betacoronavirus vaccine candidates for
further preclinical and clinical development at the end of Years 2 and 5 of our Program, respectively.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><Achievement><Achievement Attainment><Antibody Response><Antigenic Determinants><Antigens><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Biophysics><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 vaccine><COVID-19 virus><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><COVID19 vaccine><COVID19 virus><CoV-2><CoV2><Computing Methodologies><Coronaviridae><Coronavirus><Data><Development><Epitopes><Evolution><Fc Receptor><Funding><Genetic Alteration><Genetic Change><Genetic defect><Glycans><Glycoproteins><Goals><Grippe><Human><Immune response><Immunity><Immunization><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><Influenza><Influenza Vaccines><Influenza Virus><Lead><Merbecovirus><Methods><Mice><Mice Mammals><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Mosaicism><Murine><Mus><Mutation><Pb element><Performance><Phase><Phase 1/2 Clinical Trial><Phase I/II Clinical Trial><Phylogeny><Polysaccharides><Position><Positioning Attribute><Production><Proteins><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sarbecovirus><Science><Secure><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Structure><Vaccine Design><Vaccines><Variant><Variation><Viral><Work><Wuhan coronavirus><antibody receptor><base><beta CoV><beta coronavirus><beta coronavirus vaccine><betaCoV><betacoronavirus><betacoronavirus vaccine><biophysical characteristics><biophysical characterization><biophysical foundation><biophysical measurement><biophysical parameters><biophysical principles><biophysical properties><biophysical sciences><clinical development><computational methodology><computational methods><computational pipelines><computer based method><computer methods><computing method><conformation><conformational state><corona virus><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus disease 2019 vaccine><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus receptor><coronavirus vaccine><design><designing><developmental><experience><flu vaccine><flu virus vaccine><genome mutation><hCoV19><heavy metal Pb><heavy metal lead><host response><immune system response><immunogen><immunoresponse><influenza virus vaccine><influenzavirus><lead candidate><mosaic disorders><mutation scanning><mutation screening><nCoV2><nano particle><nano-sized particle><nanoparticle><nanosized particle><next generation><non-human primate><nonhuman primate><novel><panbetaCoV vaccine><pandemic><pandemic disease><pre-clinical development><preclinical development><programs><prototype><receptor binding><receptor bound><response><scaffold><scaffolding><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine against coronavirus><vaccine against flu><vaccine against influenza><vaccine candidate><vaccine for novel coronavirus><virology><β CoV><β coronavirus><β coronavirus vaccine><βCoV>